Scatter factor (SF; also known as hepatocyte growth factor [HGF], and hereinafter referred to and abbreviated as HGF/SF) is a pleiotropic growth factor that stimulates cell growth, cell motility, morphogenesis and angiogenesis. HGF/SF is produced as an inactive monomer (xcx9c100 kDa) which is proteolytically converted to its active form. Active HGF/SF is a heparin-binding heterodimeric protein composed of a 62 kDa xcex1 chain and a 34 kDa xcex2 chain. HGF/SF is a potent mitogen for parenchymal liver, epithelial and endothelial cells (Matsumoto, K, and Nakamura, T., 1997, Hepatocyte growth factor (HGF) as a tissue organizer for organogenesis and regeneration. Biochem. Biophys. Res. Commun. 239, 639-44; Boros, P. and Miller, C. M., 1995, Hepatocyte growth factor: a multifunctional cytokine. Lancet 345, 293-5). It stimulates the growth of endothelial cells and also acts as a survival factor against endothelial cell death (Morishita, R, Nakamura, S, Nakamura, Y, Aoki, M, Moriguchi, A, Kida, I, Yo, Y, Matsumoto, K, Nakamura, T, Higaki, J, Ogihara, T, 1997, Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. Diabetes 46:138-42). HGF/SF synthesized and secreted by vascular smooth muscle cells stimulate endothelial cells to proliferate, migrate and differentiate into capillary-like tubes in vitro (Grant, D. S, Kleinman, H. K., Goldberg, I. D., Bhargava, M. M., Nickoloff, B. J., Kinsella, J. L., Polverini, P., Rosen, E. M., 1993, Scatter factor induces blood vessel formation in vivo. Proc. Natl. Acad. Sci. U S A 90:1937-41; Morishita, R., Nakamura, S., Hayashi, S., Taniyama, Y., Moriguchi, A., Nagano, T., Taiji, M., Noguchi, H., Takeshita, S., Matsumoto, K., Nakamura, T., Higaki, J., Ogihara, T., 1999, Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33:1379-84). HGF/SF-containing implants in mouse subcutaneous tissue and rat cornea induce growth of new blood vessels from surrounding tissue. HGF/SF protein is expressed at sites of neovascularization including in tumors (Jeffers, M., Rong, S., Woude, G. F., 1996, Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis. J. Mol. Med. 74:505-13; Moriyama, T., Kataoka, H., Koono, M., Wakisaka, S., 1999, Expression of hepatocyte growth factor/scatter factor and its receptor c-met in brain tumors: evidence for a role in progression of astrocytic tumors Int. J. Mol. Med. 3:531-6). These findings suggest that HGF/SF plays a significant role in the formation and repair of blood vessels under physiologic and pathologic conditions. Further discussion of angiogenic proteins may be found in U.S. Pat. Nos. 6,011,009 and 5,997,868, both of which are incorporated herein by reference in their entireties.
Modulation of cellular proliferation by exogenously-supplied therapeutic agents has been offered as a new approach for the prophylaxis and/or treatment of various conditions and diseases in which limited cellular proliferation is responsible for pathology, or at least for the prolongation of rebound from a pathological state to homeostasis. For example, the duration of wound healing, normalization of myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction, development or augmentation of collateral vessel development after vascular occlusion or to ischemic tissues or organs, and vascularization of grafted or transplanted tissues, organs, or wound healing, may be accelerated by promoting cellular proliferation, particularly of vascular cells.
It is toward compounds with HGF/SF-like activity and pharmaceutical compositions comprising them for the prophylaxis and treatment of various conditions and diseases benefiting from HGF/SF activity that the present invention is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as xe2x80x9cPrior Artxe2x80x9d to the instant application.
The present invention is directed generally to compositions and pharmaceutical compositions comprising effective amounts of compounds that modulate hepatocyte growth factor/scatter factor (HGF/SF) activities in a mammal, the compounds being useful for the prophylaxis or treatment of any of a number of conditions or diseases in which HGF/SF has a therapeutically useful role. The compounds of the invention generally exhibit HGF/SF stimulatory or agonist activity.
The invention is directed to pharmaceutical compositions comprising a compound that modulates HGF/SF activity with the general formula I: 
wherein
R1 is SO2Alkyl, SO2-Aryl, COAlkyl, COAryl, CONHAlkyl; or CONHAryl; and
R3 is CHCH-heteroaryl; phenoxyphenyl; heteroaryl; or Aryl substituted heteroaryl; and a pharmaceutically-acceptable carrier, excipient or diluent.
Non-limiting examples of compounds of Formula I include
(4-chlorophenyl)[3-(2-(2-thienyl)vinyl)-1H-pyrazol-1-yl]methanone;
1-(methylsulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole;
2,2-dimethyl-1-(3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-yl)propan-1-one;
N-methyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
(4-chlorophenyl)(3-(3-phenylisoxazol-5-yl)-1H-pyrazol-1-yl)methanone;
(4-chlorophenyl)(3-(3-(4-chlorophenyl)-5-methylisoxazol-4-yl)-1H-pyrazol-1-yl)methanone;
(4-chlorophenyl)(3-(5-(2-thienyl)-2-thienyl)-1H-pyrazol-1-yl)methanone;
(2,4-dichlorophenyl)(3-(5-(2,4-difluorophenyl)-2-furyl)-1H-pyrazol-1-yl)methanone;
N1-phenyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
(4-chlorophenyl)(3-(2-(5-(2-thienyl)-2-thienyl)-4-methyl-1,3-thiazol-5-yl)-1H-pyrazol-1-yl-methanone;
(3-benzhydryl-1H-pyrazol-1-yl)(4-chlorophenyl)methanone;
N1-(4-chlorophenyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
(4-chlorophenyl)(3-(2-methylimidazo(1,2-a)pyridin-3-yl)-1H-pyrazol-1-yl)methanone;
2-chloro-6-(4-(1-(4-chlorobenzyl)-1H-pyrazol-3-yl)phenoxy)benzonitrile; and
1-((4-chlorophenyl)sulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole.
The compounds comprising the pharmaceutical compositions of the invention have been found to mimic or agonize the biological activities of HGF/SF, and thus are useful in the prophylaxis or treatment, for example, of conditions or diseases in which enhanced cellular or vascular proliferation is desirable, among other desirable activities of HGF/SF. Such conditions or diseases include hepatic disease, renal disease, bone regeneration dysfunction, poor hair growth, wound or tissue healing, treatment of various ischemic diseases, including but not limited to augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction as well as in diabetes-related ischemic conditions. The compounds are also useful in the treatment of atherosclerosis, including reduction of lipid accumulation in the vasculature. Such compounds may be administered in appropriate pharmaceutical compositions either systemically or locally to particular tissues or organs, in order to achieve the desired systemic or local effect. Such desirable activities also include induction of proliferation of endothelial cells, induction of anti-apoptotic activity, induction of scatter activity, or any combination of the foregoing activities. In a preferred embodiment, any one of these activities by a compound of the invention is reduced or inhibited in the presence of exogenous c-met receptor. Compounds of Formula I may be formulated into a suitable pharmaceutical composition for delivery as appropriate, the pharmaceutical composition containing at least one of the compounds of Formula I together with a pharmaceutically-appropriate carrier, excipient or diluent, or combinations of the foregoing. The invention is also directed to pharmaceutical dosage forms comprising an effective amount of a compound of Formula I for administration on a periodic basis, such as four times a day, three times a day, twice a day, and once a day, as well as less frequent dosing, to provide an effective amount of the compound for its intended pharmacological activity. Dosage forms administratable orally, as well as parenteral dosage forms, are embraced herein.
The invention is also directed to compounds of general formula I: 
wherein
R1 is SO2Alkyl, SO2-Aryl, COAlkyl, COAryl, CONHAlkyl; or CONHAryl; and
R3 is CHCH-heteroaryl; phenoxyphenyl; heteroaryl; or Aryl substituted heteroaryl.
Non-limiting examples of compounds of Formula I include
(4-chlorophenyl)[3-(2-(2-thienyl)vinyl)-1H-pyrazol-1-yl]methanone;
1-(methylsulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole;
2,2-dimethyl-1-(3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-yl)propan-1-one;
N-methyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
(4-chlorophenyl)(3-(3-phenylisoxazol-5-yl)-1H-pyrazol-1-yl)methanone;
(4-chlorophenyl)(3-(3-(4-chlorophenyl)-5-methylisoxazol-4-yl)-1H-pyrazol-1-yl)methanone;
(4-chlorophenyl)(3-(5-(2-thienyl)-2-thienyl)-1H-pyrazol-1-yl)methanone;
(2,4-dichlorophenyl)(3-(5-(2,4-difluorophenyl)-2-furyl)-1H-pyrazol-1-yl)methanone;
N1-phenyl-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
(4-chlorophenyl)(3-(2-(5-(2-thienyl)-2-thienyl)-4-methyl-1,3-thiazol-5-yl)-1H-pyrazol-1-yl-methanone;
(3-benzhydryl-1H-pyrazol-1-yl)(4-chlorophenyl)methanone;
N1-(4-chlorophenyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole-1-carboxamide;
(4-chlorophenyl)(3-(2-methylimidazo(1,2-a)pyridin-3-yl)-1H-pyrazol-1-yl)methanone;
2-chloro-6-(4-(1-(4-chlorobenzyl)-1H-pyrazol-3-yl)phenoxy)benzonitrile; and
1-((4-chlorophenyl)sulfonyl)-3-(2-(2-thienyl)vinyl)-1H-pyrazole.
The invention is also directed to methods for preventing or treating a disease in a mammal in which HGF/SF activity is desirable comprising administering to the mammal an effective amount of a pharmaceutical composition comprising a compound of Formula I as described hereinabove. By way of non-limiting example, conditions and diseases in which HGF/SF activity is desirable include hepatic disease, ischemic and toxin-induced renal disease, dysfunction in bone regeneration, poor hair growth, adverse wound or tissue healing, and ischemic diseases. For example, augmenting or restoring blood flow to ischemic tissues such as the heart following myocardial infarction as well as in diabetes-related ischemic conditions are amenable to treatment using the compounds of the invention. The compounds are also useful in the treatment of atherosclerosis, including reduction of lipid accumulation in the vasculature. Such desirable activities also include induction of proliferation of endothelial cells, induction of anti-apoptotic activity, induction of scatter activity, or any combination of the foregoing activities. In a preferred embodiment, any one of these activities by a compound of the invention is reduced or inhibited in the presence of exogenous c-met receptor.